[R21] Mechanisms of Axonopathy in CMT1X
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2028-05-31
Importo max: 200.413 EUR
Paese: US
Descrizione
Charcot-Marie-Tooth disease (CMT) is the eponymous designation for inherited disorders characterized
exclusively or predominantly by neuropathy. CMT affects approximately one in 2500 individuals worldwide. For
the most part, mutations in genes expressed exclusively in Schwann cells, the myelinating cell of the PNS,
produce demyelinating CMT. However, disability in all forms of CMT likely arises from axonal loss. Nonetheless,
mechanisms of axonal loss in diseases caused by mutations in Schwann cells is not well understood. This is
particularly highlighted in CMT1X, caused by mutations of GJB, the gene encoding connexin 32 (Cx32), a gap
junction protein expressed in Schwann cells but not elsewhere in the peripheral nervous system. In spite of this
Schwann cell localization, CMT1X is characterized by significant axonopathy, especially in its earliest stages.
This application is a discovery-based proposal which will integrate data from Schwann cells, other peripheral
nerve cells, and spinal motor neurons (Anterior Horn Cells, AHCs) and will provide us with insights into both
motor neuron signaling pathways as well as peripheral nerve signaling pathways which are disrupted in in the
absence of Cx32. There is currently a paucity of identified targets for ameliorating axonal loss in demyelinating
CMT, and our results will likely identify therapeutic targets to preserve axonal function in patients with CMT.
Thus, this work will form the basis for future hypothesis driven investigations to treat axonal loss, the underlying
cause of morbidity in CMT1X and all forms of CMT. In Aim 1 we ask, “what are the alterations in gene expression
that characterize the spinal motor neurons (anterior horn cells, AHCs) of CMT1X mice after onset of axonopathy
but prior to demyelination and after onset of demyelination?” We will use the RiboTag approach in conjunction
with ChAT-Cre to examine RNA expression from Anterior Horn Cells (AHCs) in the spinal cord of a Cx32
knockout mouse model of CMT1X (Cx32 KO) as well as WT and appropriate controls (ChAT-Cre or RiboTag
alone) at two and six months of age. In Aim 2 we ask, “what are the alterations in gene expression that
characterize the myelinating Schwann cells of CMT1X mouse nerve after onset of axonopathy but prior to
demyelination and after onset of demyelination? To identify cell specific signaling pathways that contribute to the
axonopathy of CMT1X we will use single nuclear RNA-seq to examine the transcriptome of the resident cells in
the sciatic nerves of WT and Cx32KO at the same timepoints as Aim 1. In Aim 3 we ask, ”how are patterns of
gene expression in anterior horn cell and peripheral nerve cell complement affected by an effective treatment of
neuropathy in a CMT1X model mouse?” We will utilize cemdomespib to investigate the effects on the patterns
of gene expression in AHCs and resident nerve cells from WT and Cx32KO mice using the same approaches
outlined in Aims 1 and 2. Thus, this work will form the basis for
Istituzione: UNIVERSITY OF ILLINOIS AT CHICAGO
PI: CHARLES K ABRAMS
Progetto: 1R21NS142944-01A1
Settori: National Institute of Neurological Disorders and Stroke
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